Association between fingertip-measured advanced glycation end products and cardiovascular events in outpatients with cardiovascular disease

Abstract Background The accumulation of advanced glycation end products (AGEs) is associated with cardiovascular events in patients with cardiovascular disease (CVD). However, the relationship between the AGEs measured by an AGEs sensor noninvasively at the fingertip and prognosis in patients with CVD remains unclear. Therefore, this study aimed to determine the relationship between AGEs score and prognosis among patients with CVD. Methods A total of 191 outpatients with CVD were included. AGEs score were measured using an AGEs sensor and the patients were classified into groups by the median value of AGEs score. The incidence of major adverse cardiovascular and cerebrovascular events (MACCE) at 30 months was compared between high- and low-AGEs score groups. In addition, receiver operating characteristic (ROC) curve analysis was used to calculate cutoff value for the AGEs score, which discriminates the occurrence of MACCE. Cox regression analysis was performed to identify the factors associated with the presence of MACCE. MACCE included cardiac death, myocardial infarction, percutaneous coronary intervention, heart failure, and stroke. Results AGEs score was normally distributed, with a median value of 0.51. No significant intergroup differences were found in laboratory findings, physical functions, or medications. The high-AGEs score group had a significantly higher incidence of MACCE than the low-AGEs score group (27.1 vs. 10.5%, P = 0.007). A high-AGEs score was a risk factor for MACCE (hazard ratio, 2.638; 95% confidence interval, 1.271–5.471; P = 0.009). After the adjustment for confounders other than 6-min walking distance, the AGEs score remained a factor associated with the occurrence of MACCE. The best cutoff AGEs score for the detection of MACCE was 0.51 (area under the curve, 0.642; P = 0.008; sensitivity, 72.2%; specificity, 54.8%). Conclusions AGEs score measured at the fingertip in patients with CVD is associated with MACCE. AGEs score, which can be measured noninvasively and easily, may be useful as an assessment for the secondary prevention of CVD in patients with CVD

Advanced Glycation End Products Are Associated with Diabetes Status and Physical Functions in Patients with Cardiovascular Disease

Advanced glycated end products (AGEs) accumulate systemically and cause diabetes complications. However, whether noninvasive measurable AGEs are associated with diabetes status and physical functions remains unclear. One hundred and ten patients with cardiovascular disease (CVD) who underwent outpatient cardiac rehabilitation were included. AGEs scores, using AGEs sensors, were evaluated concomitantly with a physical evaluation, including testing the isometric knee extension strength (IKES) and 6 min walking distance (6MWD). Thirty-three (30%) patients had a history of diabetes mellitus (DM). The AGEs score was not different in the presence of DM history (0.52 ± 0.09 vs. 0.51 ± 0.09, p = 0.768) and was not correlated with blood glucose (r = 0.001, p = 0.995). The AGEs score was positively correlated with hemoglobin A1c (HbA1c, r = 0.288, p = 0.004) and negatively correlated with physical functions (IKES, r = −0.243, p = 0.011; 6MWD, r = −0.298, p = 0.002). The multivariate analysis demonstrated that 6MWD was independently associated with a high AGEs score (>0.52). The AGEs score was associated with HbA1c, IKES, and 6MWD in patients with CVD. The AGEs score might be a useful indicator for evaluating not only glycemic control but also physical functions

Targeting hepatic oxidative stress rescues bone loss in liver fibrosis

Objective: Chronic liver diseases often involve metabolic damage to the skeletal system. The underlying mechanism of bone loss in chronic liver diseases remains unclear, and appropriate therapeutic options, except for orthotopic liver transplantation, have proved insufficient for these patients. This study aimed to investigate the efficacy and mechanism of transplantation of immature hepatocyte-like cells converted from stem cells from human exfoliated deciduous teeth (SHED-Heps) in bone loss of chronic liver fibrosis. Methods: Mice that were chronically treated with CCl4 received SHED-Heps, and trabecular bone density, reactive oxygen species (ROS), and osteoclast activity were subsequently analyzed in vivo and in vitro. The effects of stanniocalcin 1 (STC1) knockdown in SHED-Heps were also evaluated in chronically CCl4 treated mice. Results: SHED-Hep transplantation (SHED-HepTx) improved trabecular bone loss and liver fibrosis in chronic CCl4-treated mice. SHED-HepTx reduced hepatic ROS production and interleukin 17 (Il-17) expression under chronic CCl4 damage. SHED-HepTx reduced the expression of both Il-17 and tumor necrosis factor receptor superfamily 11A (Tnfrsf11a) and ameliorated the imbalance of osteoclast and osteoblast activities in the bone marrow of CCl4-treated mice. Functional knockdown of STC1 in SHED-Heps attenuated the benefit of SHED-HepTx including anti-bone loss effect by suppressing osteoclast differentiation through TNFSF11–TNFRSF11A signaling and enhancing osteoblast differentiation in the bone marrow, as well as anti-fibrotic and anti-ROS effects in the CCl4-injured livers. Conclusions: These findings suggest that targeting hepatic ROS provides a novel approach to treat bone loss resulting from chronic liver diseases

Additional file 1 of Association between fingertip-measured advanced glycation end products and cardiovascular events in outpatients with cardiovascular disease

Additional file 1: Figure S1. Study flowchart. AGEs; advanced glycation end products. Figure S2. Normality test of advanced glycation end products (AGEs) score by Kolmogorov–Smirnov test. The average AGEs score was 0.51, and the median value was 0.51, indicating a normal distribution (P = 0.200). Figure S3. Kaplan–Meier curves show the comparison of the incidence of cardiovascular events in the high- and low-advanced glycation end products (AGEs) groups. The incidence of all-cause death (A, 9.4 vs. 4.2%, P = 0.296), cardiac death (B, 5.2 vs. 2.1%, P = 0.317), heart failure (C, 16.7 vs. 9.5%, P = 0.185), stroke (D, 1.0 vs. 0.0%, P = 0.156) were not significantly different between the high- and low-AGEs groups. Table S1. Baseline clinical characteristics. Table S2. Univariate analysis of factors associated with MACCE. Table S3. Multivariate analysis of factors associated with MACCE in physical functions. Table S4. Multivariate analysis of factors associated with MACCE

A proposed simple screening method to determine relative contributions of CYP3A4 and CYP3A5 to drug metabolism in vitro

Purpose The cytochrome P450 (CYP) 3A family of enzymes metabolize the majority of clinically used drugs. CYP3A4 and CYP3A5 are the two major CYP3A isoforms, but exhinbit different substrate specificity. The aim of this study was to establish a simple screening method to determine the relative contributions of CYP3A4 and CYP3A5 to drug metabolism in vitro. Methods A screening method was developed based on competitive inhibition using luciferin-PPXE (L-PPXE), a luminogenic CYP3A substrate. CYP3cide, tacrolimus, and midazolam were selected as standard compounds metabolized by CYP3A4 or CYP3A5. Nine clinically-used drugs were evaluated for their abilities to inhibit luminescence resulting from L-PPXE metabolism. Appropriate reaction conditions for the screening method were determined using recombinant CYP3A4 and CYP3A5. Results A significant decrease in luminescence resulting from L-PPXE metabolism by CYP3A4 and CYP3A5 was observed only for drugs reported to be metabolized by CYP3As. The substrate specificities of CYP3A4 or CYP3A5 for the proposed CYP3A substrates using our screening method were consistent with those of previous reports or available drug information from pharmaceutical companies. The reaction volume for this method was 50 μL, and the time required for the entire procedure was 70 min. Furthermore, this screening can be performed using a single tube with minimal training. Conclusions Through the establishment of our screening method in the present study, we are sure it is useful to determine the relative contributions of CYP3A4 and CYP3A5 to drug metabolism in vitro

Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment

Background Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.Methods We used multiplexed immunofluorescence combined with digital image analysis to identify CD14+ monocytic and CD15+ granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1–Q4) of myeloid cell densities. Immune cell–tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.Results Higher intraepithelial (Ptrend=0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal (Ptrend <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14+HLA-DR+ cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14+HLA-DR− cells were associated with higher colorectal cancer-specific mortality (Ptrend=0.0003; HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15+ cells were located closer to tumor cells than CD14+ cells, and CD14+HLA-DR+ cells were closer to tumor than CD14+HLA-DR− cells (p<0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14+HLA-DR+ cell versus CD14+HLA-DR− cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality (Ptrend <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).Conclusions Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14+HLA-DR+ and immature CD14+HLA-DR− monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment